1. Field of the Invention
The present invention is broadly directed to a method for enhancing anti-neoplasm effects of chemotherapies and radiation therapies with PKC inhibitors. The present invention is particularly directed to the use of Protein Kinase C (PKC) inhibitors, especially a particular class of isozyme selective PKC inhibitors in combination with an oncolytic agent or .gamma.-irradiation to enhance their anti-neoplasm effects in treatment of neoplasms.
2. Description of Related Art
Therapeutic treatments have been developed over the years to treat neoplasms. There are two major approaches to treat neoplasms: 1) chemotherapy employing oncolytic agents, and 2) radiation therapy, e.g., .gamma.-irradiation. Oncolytic agents and .gamma.-irradiation cause cytotoxic effects, preferentially to tumor cells, and cause cell death.
Studies have shown that .gamma.-irradiation and certain groups of oncolytic agents assert their cytotoxic effects by activating programmed cell death or apoptosis. A balance between the activities of apoptotic and antiapoptotic intracellular signal transduction pathways is important towards a cell's decision of undergoing apoptosis in response to the above mentioned chemotherapy as well as radiation therapy.
PKC inhibitors has been proposed for cancer therapy, e.g. see U.S. Pat. No. 5,552,391, and PKC activities have been indicated to exert antiapoptotic effects, especially in response to radiation therapies, e.g., .gamma.-irradiation. In particular, studies have shown that activation of PKC inhibits apoptosis induced by anti-neoplasm agents such as Ara-c, 2-chloro-2-deoxyadenosine, 9-.beta.-D-arabinosyl-2-fluoroadenine, and .gamma.-irradiation therapy. There also have been indications that down regulation of PKC activities in tumor cells enhances apoptosis stimulated by oncolytic agents. PKC activation has been shown to attenuate .gamma.-irradiation induced cell death.
There is a need in the art to develop therapeutic agents which enhance the apoptotic signal transduction pathways in cells and thereby enhance the clinical efficacy of oncolytic agents and radiation therapy.